Characterization of in vitro and in vivo metabolism of leelamine using liquid chromatography-tandem mass spectrometry

Shrestha, Riya; Jo, Jung Jae; Lee, DooHyun; Lee, Tae‐Ho; Lee, Sangkyu

doi:10.1080/00498254.2018.1480816

Cited by 6 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The adamantyl moiety is known to be the major site for metabolic oxidation in numerous in vitro and in vivo metabolism and pharmacokinetic studies, while the adamantyl bridgehead tertiary carbons are generally believed to be the preferred oxidation site for CYP mediated metabolism (Rohde et al, 2007;Gandhi et al, 2015;Mardal et al, 2018;Shrestha et al, 2018). Conversely, as we have earlier reported (Honrao et al, 2015;Honrao et al, 2016), we now provide detailed evidence that secondary adamantyl carbons can also be the primary site for oxidative metabolism.…”

Section: Introductionsupporting

confidence: 73%

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

Honrao

Kulkarni

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Adamantyl groups are key structural subunit commonly used in many marketed drugs targeting diseases ranging from viral infections to neurological disorders. The metabolic disposition of adamantyl compounds has been mostly studied using LC-MS based approaches. However, metabolite quantities isolated from biological preparations are often insufficient for unambiguous structural characterization by NMR. In this work, we utilized microcoil NMR in conjunction with LC-MS to characterize liver microsomal metabolites of an adamantyl based CB2 agonist AM9338, 1-(3-(1H-1,2,3-triazol-1-yl) propyl)-N-(adamantan-1-yl)-1H-indazole-3-carboxamide, a candidate compound for potential multiple sclerosis treatment. We have identified a total of 9 oxidative metabolites of AM9338 whereas mono- or di-hydroxylation of the adamantyl moiety is the primary metabolic pathway. While it is generally believed that the tertiary adamantyl carbons are the preferred sites of CYP450 oxidation, both the mono- and di-hydroxyl metabolites of AM9338 show that the primary oxidative sites are located on the secondary adamantyl carbons. To our knowledge this di-hydroxylated metabolite is a novel adamantyl metabolite that has not been reported before. Further, the stereochemistry of both mono- and di-hydroxyl adamantyl metabolites has been determined using NOE correlations. Furthermore, docking of AM9338 into the CYP3A4 metabolic enzyme corroborates with our experimental findings, and the modelling results also provide a possible mechanism for the unusual susceptibility of adamantyl secondary carbons to metabolic oxidations. The novel dihydroxylated AM9338 metabolite identified in this study, along with the previously known adamantyl metabolites, gives a more complete picture of the metabolic disposition for adamantyl compounds.

show abstract

Section: Introductionsupporting

confidence: 73%

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

Honrao

Kulkarni

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Out of 78 articles included in the analysis (42 in vitro, 42 in vivo, and 16 clinical studies), 47 (60.3%), 14 (17.9%) and 17 (21.8%) articles respectively, investigated metabolite profiles of conventional anticancer drugs/synthetic anticancer candidates, small-molecules targeted therapy, and herbderived compounds with anticancer activities. These studies involved a total of 57 (57.0%) conventional anticancer drugs/ synthetic anticancer candidates, 6, 22 (22.0%) studies for small-molecules targeted therapy, 4,5,[59][60][61][62][63][64][65][66][67][68][69][70] and 21 (21.0%) studies for herb-derived compounds with anticancer activities 2,3,7,9,[71][72][73][74][75][76][77][78][79][80][81][82][83] (Tables 1-3). Anticancer drugs or candidate compounds are metabolized by either Phase I, or phase II metabolizing enzyme alone, or both phase I and phase II metabolizing enzymes.…”

Section: Study Descriptionmentioning

confidence: 99%

“…[2][3][4][5][6] As herb-derived anticancer drugs are considered to be less toxic compared with synthetic drugs, attentions to developing new drugs originating from herbal products have substantially been paid worldwide. These include leelamine, the natural active compound from the bark of pine tree, 7 atractylodin and β-eudesmol, the natural active compounds from rhizomes of Atractylodes lancea (Thunb) DC, 8 and alantolactone, an active sesquiterpene from Inula helenium L. 9 Drug metabolism and pharmacokinetic (DMPK) studies play an important role in all steps of drug discovery and development, including anticancer drugs. 10 Metabolism is the process of which xenobiotics or endogenous substances in the body are biotransformed to the metabolic products that facilitate their elimination.…”

Section: Introductionmentioning

confidence: 99%

Metabolite Profiling in Anticancer Drug Development: A Systematic Review

Muhamad

Na‐Bangchang

2020

DDDT

View full text Add to dashboard Cite

Drug metabolism is one of the most important pharmacokinetic processes and plays an important role during the stage of drug development. The metabolite profile investigation is important as the metabolites generated could be beneficial for therapy or leading to serious toxicity. This systematic review aims to summarize the research articles relating to the metabolite profile investigation of conventional drugs and herb-derived compounds for cancer chemotherapy, to examine factors influencing metabolite profiling of these drugs/compounds, and to determine the relationship between therapeutic efficacy and toxicity of their metabolites. The literature search was performed through PubMed and ScienceDirect databases up to January 2019. Out of 830 published articles, 78 articles were included in the analysis based on pre-defined inclusion and exclusion criteria. Both phase I and II enzymes metabolize the anticancer agents/herb-derived compounds. The major phase I reactions include oxidation/hydroxylation and hydrolysis, while the major phase II reactions are glucuronidation, methylation, and sulfation. Four main factors were found to influence metabolite formation, including species, gender, and route and dose of drug administration. Some metabolites were identified as active or toxic metabolites. This information is critical for cancer chemotherapy and anticancer drug development.

show abstract

“…CYP 2D6 was identified to be the dominant CYP enzyme that allows the biotransformation of leelamine to its hydroxylated metabolite, in comparison to the other major isoforms. Interestingly, only one metabolite has been identified so far in urine, and none in feces, thus suggesting that leelamine is metabolized to a mono-hydroxyl metabolite by CYP2D6 and principally excreted in the urine [87].…”

Section: Metabolism and Toxicity Studiesmentioning

confidence: 99%

A Brief Overview of the Antitumoral Actions of Leelamine

et al. 2019

View full text Add to dashboard Cite

For the last couple of decades, natural products, either applied singly or in conjunction with other cancer therapies including chemotherapy and radiotherapy, have allowed us to combat different types of human cancers through the inhibition of their initiation and progression. The principal sources of these useful compounds are isolated from plants that were described in traditional medicines for their curative potential. Leelamine, derived from the bark of pine trees, was previously reported as having a weak agonistic effect on cannabinoid receptors and limited inhibitory effects on pyruvate dehydrogenase kinases (PDKs). It has been reported to possess a strong lysosomotropic property; this feature enables its assembly inside the acidic compartments within a cell, such as lysosomes, which may eventually hinder endocytosis. In this review, we briefly highlight the varied antineoplastic actions of leelamine that have found implications in pharmacological research, and the numerous intracellular targets affected by this agent that can effectively negate the oncogenic process.

show abstract

Characterization of in vitro and in vivo metabolism of leelamine using liquid chromatography-tandem mass spectrometry

Cited by 6 publications

References 20 publications

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite

<p>Metabolite Profiling in Anticancer Drug Development: A Systematic Review</p>

A Brief Overview of the Antitumoral Actions of Leelamine

Contact Info

Product

Resources

About